Vitamin D Synthesis

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Overview

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Step-by-Step Pathway

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Details at Each Step

1 & 2 — Skin (Photosynthesis)

• Epidermal 7-dehydrocholesterol absorbs UV-B radiation (280–315 nm) and is photolyzed to pre-vitamin D₃.
• Pre-vitamin D₃ then undergoes spontaneous thermal isomerization to form the stable vitamin D₃.
• Vitamin D₃ diffuses into dermal capillaries and enters systemic circulation.

Key point: Prolonged UV exposure does NOT cause vitamin D toxicity — excess pre-vitamin D₃ and vitamin D₃ are degraded by UV light into inactive photoproducts (lumisterol, tachysterol).

3 — Liver (First Hydroxylation)

• Vitamin D₃ (from skin or diet) is hydroxylated at C-25 to form calcifediol (25-hydroxyvitamin D₃).
• This is the major circulating form and the standard lab test for vitamin D status.
• The reaction is largely unregulated — serum 25(OH)D reflects body stores/input.

4 — Kidney (Second Hydroxylation — Rate-Limiting Step)

• Calcifediol is hydroxylated at C-1α to form calcitriol (1,25-dihydroxyvitamin D₃) — the biologically active form.
• CYP27B1 (1α-hydroxylase) is tightly regulated:
  • ↑ by: PTH, low serum calcium, low serum phosphate, prolactin, growth hormone
  • ↓ by: calcitriol itself (negative feedback), FGF-23, high calcium/phosphate

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Dietary Sources (Exogenous Pathway)

• Vitamin D₂ (ergocalciferol): from plant sources (UV-irradiated fungi/yeast)
• Vitamin D₃ (cholecalciferol): from animal sources (fatty fish, egg yolk, fortified milk)
• Both enter the same hepatic and renal hydroxylation pathway.

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Physiological Effects of Calcitriol (1,25(OH)₂D₃)

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Clinical Relevance

• Deficiency causes: rickets (children), osteomalacia (adults), secondary hyperparathyroidism
• Factors reducing synthesis: dark skin (melanin blocks UV-B), high latitude/winter, sunscreen, aging (↓ skin 7-dehydrocholesterol), chronic kidney disease (↓ CYP27B1), liver disease (↓ CYP2R1)
• Toxicity: almost always from supplementation, not sun exposure; causes hypercalcemia

Blood Products and Their Uses

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Overview of Major Blood Products

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1. Packed Red Blood Cells (pRBCs)

• Acute blood loss — to restore circulating volume and oxygen delivery
• Perioperative anaemia — maintaining adequate O₂ delivery during surgery
• Symptomatic chronic anaemia — without haemorrhage or impending surgery

Restrictive transfusion strategies are preferred — transfuse to symptoms, not numbers alone.

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2. Fresh Frozen Plasma (FFP)

• PT or aPTT > 1.5× the reference range with active bleeding or prior to invasive procedure
• Massive transfusion protocol (MTP) — typically given in 1:1:1 ratio with pRBCs and platelets
• Reversal of warfarin (when PCC unavailable)
• TTP (Thrombotic Thrombocytopenic Purpura) — as plasma exchange fluid
• Liver disease with coagulopathy and bleeding

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3. Platelets

• Therapeutic: Active bleeding with platelet count < 50,000/µL, or platelet dysfunction (e.g., aspirin, uremia)
• Prophylactic: Platelet count < 20,000/µL in stable patients; < 50,000/µL pre-procedure; < 100,000/µL pre-neurosurgery or ophthalmologic surgery

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4. Cryoprecipitate

• Fibrinogen deficiency: fibrinogen < 100 mg/dL (some guidelines use < 150–200 mg/dL in active bleeding)
• Disseminated Intravascular Coagulation (DIC)
• Haemophilia A and von Willebrand disease (when specific concentrates unavailable)
• Massive hemorrhage / obstetric hemorrhage

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5. Albumin

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6. Prothrombin Complex Concentrate (PCC)

• 4-factor PCC: Rapid reversal of warfarin (preferred over FFP — faster, lower volume)
• 3-factor PCC: Factors II, IX, X (less Factor VII)
• Also used for reversal of direct oral anticoagulants (DOACs) in life-threatening bleeding

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Massive Transfusion Protocol (MTP)

• Standard ratio: pRBCs : FFP : Platelets = 1:1:1
• Consider Tranexamic acid (TXA) early (within 3 hours of injury)
• Monitor with thromboelastography (TEG/ROTEM) for targeted therapy
• Correct hypothermia, acidosis, hypocalcaemia (the "lethal triad")

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Transfusion Reactions

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Special Modifications of Blood Products

Timing of Surgery for Neck of Femur (NOF) Fracture

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The Core Principle: "As Soon As Medically Safe"

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Key Guideline Recommendations

Bottom line: Most major guidelines target < 36–48 hours. The UK NICE guideline specifically sets 36 hours as the benchmark for audit purposes.

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Why Timing Matters

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Special Case: Young / Active Patient with Displaced Femoral Neck Fracture

• The femoral head blood supply (mainly via medial femoral circumflex artery) is disrupted by displacement.
• Urgent reduction and internal fixation within 6–12 hours is traditionally recommended to restore blood flow and prevent AVN.
• Some evidence supports emergency surgery (< 6 hours) in young patients to preserve the native femoral head.
• In practice, many centres aim for < 24 hours even in young patients if logistics delay emergency fixation.

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Does Accelerated Surgery (< 6 hours) Help in Elderly?

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Acceptable Reasons to Delay Beyond 36–48 Hours

• Uncontrolled anticoagulation (warfarin: wait for INR < 2; DOACs: guidance varies — delay not clearly beneficial)
• Severe electrolyte disturbance
• Decompensated heart failure or uncontrolled arrhythmia
• Active chest infection requiring treatment
• Unstable angina / recent MI

Delay is NOT justified for: mild anaemia alone, diet-controlled diabetes, stable chronic conditions, or out-of-hours timing (meta-analysis shows no difference in outcomes for daytime vs. after-hours surgery) (Management of Severe Peri-Operative Bleeding, p. 38).

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Summary